Fig. 7. Proposed model depicting the role of ESRRB at SEs in pluripotent stem cells.

In naive pluripotent cells, the dynamic expression and binding of the nuclear receptor ESRRB instigates a metastable state at DM subregions (magenta) by counteracting DNMT3s activities as reflected in cell-to-cell CpG methylation heterogeneity. In contrast, PU subregions (green) consist of hotspots of core and naive pluripotency TF binding and remain stably unmethylated. Upon ESRRB depletion and/or during the establishment of primed pluripotency, DM subregions are rapidly and selectively destabilised with the loss of mediator occupancy and consolidation of CpG methylated state, leading to their decommissioning in primed epiblast cells. In contrast, PU subregions remain unmethylated and highly bound by core and primed pluripotency TFs, indicative of their continued enhancer activity. The partitioning of enhancer units within SEs as constitutively active (PU) or decommissioned (DM) proposes a mechanism by which the pluripotency transcriptional programme can be partially reset during the naive-to-primed transition, preserving pluripotency as cells prepare for subsequent differentiation. Core (OCT4 and SOX2), naive (ESRRB, KLF4 and NANOG) and primed (OCT6 and OTX2) pluripotency TFs are represented along with the mediator protein complexes (MED), DNMT and TET enzymes.